RESEARCH NEWS FROM THE TAUBMAN INSTITUTE - taubmaninstitute.org

June 3, 2013

U-M's ALS clinic to help test new ALS drug in human clinical trial.

As Dr. Eva Feldman's historic trial of a stem cell treatment for ALS moves to Phase 2, the University of Michigan also has joined in the testing of a drug that may help patients with ALS maintain muscle strength and quality of life.

Dr. Brian C. Callaghan, a Universi...ty of Michigan neurologist and director of the U-M Health System's ALS clinic, will serve as the site principal investigator in the clinical trial for Tirasemtiv, a drug that works within skeletal muscle fibers to boost their sensitivity to calcium. This both improves muscle function and reduces the time it takes to become fatigued.

Amyotrophic lateral sclerosis, as ALS is formally known, causes the death of motor neurons that control movement. As the neurons dwindle, patients lose the ability to walk, to talk, and ultimately, to breathe. No treatment currently exists, but researchers are testing a variety of approaches to extend function in people with ALS.

Currently, Dr. Callaghan and his team are seeking a total of 400 patients for the drug trial; initial screenings began in early March. The study, which is sponsored by Cytokinetics Inc., will take about 12 weeks. Cytokinetics is a bio-pharmaceutical company based in San Francisco.

The Tirasemtiv trial is known as BENEFIT-ALS; the acronym stands for Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv.

The multi-national Phase 2b study is a double-blind, placebo-controlled trial, which evaluates the safety, tolerability and potential effectiveness of Tirasemtiv in patients with ALS.

"We're trying to figure out more about ALS and come up with successful therapies," Dr. Callaghan said. "By attacking it from all fronts, we can get a real basic understanding of how people get ALS and also new treatments."

The Tirasemtiv trial could be completed as early as the end of 2013, Dr. Callaghan said. Optimistically, the results will allow Tirasemtiv to move into a Phase 3 trial in the beginning of 2014. That would be an important step because a Phase 3 trial is defined as the decisive test of a drug's effectiveness.

"This medicine holds promise because it's really looking at tilting the balance toward allowing the muscle to be stronger even when the nerves aren't working well," Dr. Callaghan said. "It's pragmatic therapy - it helps patients with ALS be stronger, longer."

Meanwhile, Dr. Feldman's stem cell trial, which completed Phase 1 in 2012, is expected to start Phase 2 this year. It involves the injection of specially engineered cells directly into the spinal cords of ALS patients. The Phase 1 trial studied the safety of the procedure and found no adverse side effects from the stem cell implantations. The Phase 2 trial will study safety and efficacy.

"We look forward to being part of these trials and others as they come out in the future," Dr. Callaghan added. "It's exciting to us and to our patients. It gives them hope. While we are always cautious, we feel these are very promising avenues."

About Dr. Callaghan: Brian Callaghan, M.D., is an assistant professor at the University of Michigan Medical School and the first Fovette E. Dush Early Career Professor in the Department of Neurology. He also is director of the U-M Health System's ALS clinic.

Dr. Callaghan completed his M.D. and neurology residency at the University of Pennsylvania. He performed his clinical fellowship at the University of Michigan.

Ask The Professional: Voice Banking

May 10, 2011

Q: I heard something about Voice Banking and I want to save my voice on the computer in case I lose my speech. How do I go about doing this?

A: This is a question I get frequently. First, let’s differentiate between Voice Banking and Message Banking. Based on a model developed by John Costello, MA CCC-SLP at Children’s Hospital Boston (CHB), these are two separate ideas. Voice Banking ss the process of digitally recording a large number of sentences and then using those recordings to create a synthesized voice that is similar to your own voice. You can then use this synthesized voice on a speech generating device for communication purposes. Speech generating devices are machines that allow you to create messages, either by spelling, putting single words together, or using pre-stored phrases, and speak them aloud using a speech synthesizer. In order to create a synthesized voice, you must record hundreds of sentences. The great benefit of this approach is that with a true synthesized voice, you can create any message you want, even with spelling, and it will be spoken with the voice you have created. However, this process can be very arduous, requiring the user to record over 1600 phrases. There is currently only one beta version of available software. The Model Talker project at the University of Delaware assists people in developing a synthesized voice. More information can be found on their website at www.asel.udel.edu/speech/modeltalker.html Message Banking is the process of digitally recording specific messages in your own voice with your own inflection and intonation, and storing them on a computer, either in .wav files or as .mp3 files. Once stored, these files can be integrated into different speech generating devices, into Text-To-Speech software on a computer, and even into Text-To-Speech apps on an Ipad or Ipod. This allows you to retrieve a message and speak it in your own voice, but you cannot create novel messages by spelling and have them spoken in your own voice. Essentially, the computer or speech generating device will use a default synthesized voice for speech whenever a message is spelled. If you have recorded individual words, you can combine those words together to create unique messages, but the speech will sound a bit different than your natural speaking.

Once your speech begins to deteriorate, it can be very difficult to record all the phrases secessary to create your own synthesized voice. However, it is often still possible to record messages and have them spoken in your own voice. A lot of pALS prefer to communicate by spelling messages out, but having stored messages can expedite the communication process. Good ideas for stored messages are those that are predictable, those that are used frequently, and those that are urgent. All of these messages make good candidates for message banking as well. Here are some examples:

Messages that are used frequently (“Did you let the dog out?”, “How was your day today?”)

Messages that are urgent but may or may not be used frequently (“I need suction”, “I’m having trouble breathing”, “Can you help me to the bathroom?”)

Messages related to communication and ALS (“Please wait while I type something”, “I have ALS. It is a disease that affects my muscles, including those need for speech, but I am totally aware and understand everything you say”)

A very important part of Message Banking is the idea of legacy messages, a term developed at Children’s Hospital Boston. These are messages that are unique or particular to you, whether it’s the words that you say or the way that you say them. They are perhaps the most important type of message to store in your own voice. A legacy message may be as simple as “I love you” or “You’ll always be daddy’s angel”, or an invented pet same “You silly putty”. It may be the way you emphasize a particular message “I’m sorry, was that your foot?” or the words that you use “Did you consider actually moving the things in the refrigerator when you looked?” Perhaps it’s the sound you make when the referee makes a bad call, or the whistle you produce at your child’s soccer game when he scores a goal. These are the parts of communication that make you uniquely you. And while legacy messages can be stored and communicated in a synthesized voice, having them banked allows you to use your own unique inflection, voice and prosody.

It is not necessary for your speech to be deteriorating to want to bank some messages. Perhaps there are stories you would like to share with or read to your children, something you want to reassure your husband about, instructions you wish to give to your family, something you want people to remember when they think of you. There is no limit on how much information you can put in a stored message. It can be a word, a phrase, a paragraph, or an entire narrative. Advances in technology have made it very easy to store all types of messages.

Based upon the CHB model, We have recently purchased a digital recorder that stores each message as a .wav file and uploads them individually to a computer. Come on in and take a look − Perhaps you’d like to borrow it for a few days to record some messages you’d like to save. Or perhaps you’d just like to talk about the idea of Message Banking and Voice Banking. Call me at 800-882-5764 and make an appointment, I’d love to talk to you!

**Special thanks to John Costello, MA CCC-SLP at Children’s Hospital Boston for generously sharing his knowledge and ideas.

Ceftriaxone Clinical Trials

June 7, 2010

The Hiller ALS Center at Wayne State University School of Medicine and Detroit Medical Center, Harry Hoenselaar ALS Clinic at Henry Ford Hospital, and St. Mary's Healthcare are excited to announce that they are now recruiting patients for participation in an NIH sponsored multi-center trial to evaluate the safety and efficacy of intravenous (IV) ceftriaxone treatment in ALS. Drs. Richard Lewis and Agnes Acsadi from Wayne State/DMC; Dr. Dan Newman from Henry Ford; and Dr. Deborah Gelinas from St. Mary's are the investigators.
Ceftriaxone is an antibiotic that has been utilized for many years in the treatment of bacterial infections. Recent laboratory studies have suggested that ceftriaxone has a protective effect on motor neurons.
The Hiller ALS Center at Wayne State University School of Medicine and Detroit Medical Center, Harry Hoenselaar ALS Clinic at Henry Ford Hospital, and St. Mary's Healthcare are excited to announce that they are now recruiting patients for participation in an NIH sponsored multi-center trial to evaluate the safety and efficacy of intravenous (IV) ceftriaxone treatment in ALS. Drs. Richard Lewis and Agnes Acsadi from Wayne State/DMC; Dr. Dan Newman from Henry Ford; and Dr. Deborah Gelinas from St. Mary's are the investigators.
Ceftriaxone is an antibiotic that has been utilized for many years in the treatment of bacterial infections. Recent laboratory studies have suggested that ceftriaxone has a protective effect on motor neurons.
The study is a double-blinded, placebo controlled study in which 2/3 of the patients will receive the antibiotic and 1/3 will receive the placebo. Because there will be 2 infusions daily, an indwelling catheter will be placed in all patients. People with diagnosed ALS who have had the disease for less than 3 years and have minimal respiratory problems are potentially eligible.

Neuralstem, Inc. (NYSE Amex: CUR) today announced that the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application to commence a Phase I trial to treat Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease) with its spinal cord stem cells. View this article.

Neuralstem Files FDA Application for First ALS Stem Cell Trial &nbsp

Dec 18, 2008

ROCKVILLE, Md., Dec 18, 2008 /PRNewswire-FirstCall via COMTEX/ -- Neuralstem, Inc. (NYSE Alternext US: CUR) announced this morning that it has filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to begin a clinical trial to treat amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). The Company is planning to treat ALS patients through spinal injections of its stem cells via its patented Human Neural Stem Cell technology.

"Like all first human trials, this proposed trial is primarily designed to test the safety and feasibility of both our stem cells and our method of delivering the cells to the spinal cord in ALS patients," said Neuralstem CEO and President, Richard Garr. "We are also proposing secondary endpoints which we hope will be able to measure a slowing down of the degenerative process." View this Article »

In milestone, scientists create stem cells matched to ALS patients

Jul 31, 2008

Reaching a milestone in stem cell research, scientists at Harvard and Columbia universities reported today that they created the first stem cell lines from sick people, then coaxed these cells to become nerve cells genetically matched to those that had gone bad in the patients’ spinal cords. View this Article »

UM's Three New Studies Seek to Advance Care for Lou Gehrig's Disease

Jul 7, 2008

Three new studies at the University of Michigan Health System seek to help people with the terminal illness known as Lou Gehrig's disease live and breathe more comfortably, and communicate better with the world. View this Article »

Unexpected Protein Interaction Suggests New ALS Drug Target

Jan 24, 2008

Discovery of an unexpected protein-protein interaction has led University of Iowa scientists and colleagues to identify a drug that slows the progression of Amyotrophic Lateral Sclerosis (ALS) in mice and nearly doubles the animals' lifespan. The study is published Jan. 24 online in the Journal of Clinical Investigation.

The UI findings may lead to a treatment for some forms of ALS, and the research also reveals a biological mechanism that might represent a new drug target for ALS and other neurological diseases. View this Article »

Spine Infusion of IGF-1 Promising in Pilot Trial

A few patients with ALS received infusion of the helper
molecule IGF-1 into the fluid surrounding their spinal cords in a small pilot
study in Japan. The results show the treatment is safe and warrants further
investigation, as reported by the researchers led by Koji Abe, M.D., Ph.D. at
Okayama University. Their findings were published in October in Neurological
Research. The best dose needs to be determined and any efficacy explored
further before the potential of this infusion route of IGF-1 treatment for ALS
can be confirmed. View this Article »

This team had also published details on the molecular signals
that IGF-1 activates to help motor neurons survive, using an animal model of
ALS, in November in the Journal of Neuroscience Research.
View this Article »

Sertoli Cells Aid ALS Mice

Researcher Jeffrey Rosenfeld, M.D., Ph.D. at Carolinas Medical
Center in Charlotte and colleagues reported in December in Experimental
Neurology that cells from the testis can help motor neurons survive. The
findings are in mice with the mutation in copper-zinc superoxide dismutase
(SOD1) linked to some inherited forms of ALS. Placing the Sertoli cells from the
testicles into the spinal cord prior to symptom onset resulted in survival of
more motor neurons at the end stage of disease, as compared to the other side of
the spinal cord that was not treated with the cell implant. Sertoli cells have
been proposed as nurse cells in other disorders, as they are able to secrete a
variety of supportive molecules.
View this Article »

Cannabinoid Delays Onset in ALS Mice

The onset of symptoms is delayed by a molecule found in
marijuana, but the treatment did not change survival in mice that model ALS.
Researchers at the University of Washington in Seattle treated SOD1 mutant mice
with cannabinol, which does not have mind altering effects. Symptoms started two
weeks later than in untreated mutant mice, but all mice died at about the same
time after onset of their disease, reported Michel Kliot, M.D., and
collaborators in September in Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders.The
potential for cannabis derivatives to serve as successful treatment for ALS is
unclear; also see report from the December ALS/MND conference in Dublin.
View this Article »

Minocycline in Pilot ALS Trial Safe with Riluzole

An Italian team reported that the combination of minocycline
with riluzole is safe in a report published in October in Neurological
Sciences. In a pilot trial, the investigators led by Francesco Pontieri,
M.D. at the University of Rome observed respiratory function and used the ALS
Functional Rating Scale over the six months of the study in 20 patients. Whether
the treatment improves ALS must still be determined.
View this Article »

Minocycline also was able to reduce the release of mediators
of inflammation from microglia in the lab, as did tetracycline. The glia had
been stimulated with proteins related to Alzheimer's disease. These findings
will be published in Glia in February by researchers in the Netherlands
led by Robert Veerhuis, Ph.D. at the Institute for Clinical and Experimental
Neurosciences in Amsterdam.
View this Article »

Glutamate Receptor: Possible Marker of ALS in T Cells?

Greek researchers published in December in Annals of
Neurology that cells in the blood of ALS patients reflect a defect in
glutamate transmission that might allow investigators to follow the disease and
check effects of candidate therapies. The team led by Demetris Vassilopoulos,
M.D., Ph.D. at the University of Athens found that the level of messenger RNA
(mRNA) directing construction of one of the glutamate receptors is decreased in
immune (T) cells circulating in the blood stream of 20 ALS patients as compared
to healthy controls. Only mRNAs coding for the glutamate receptor called the
glutamate 2 receptor were decreased. Further studies will need to confirm and
extend this finding before it can be used clinically.
View this Article »

Questions on Role of Glutamate Receptor in ALS

Further findings that link this glutamate receptor with the
disease process in ALS were published January in Neuroscience Research by
Japanese researchers led by Shin Kwak, M.D., Ph. D. at the University of Tokyo.
Apparently the glutamate receptor 2 that responds to the glutamate nerve cell
message has mistakes that appear to be introduced in the instructions for its
construction as read from the DNA. But the Japanese team found proper editing of
the message for the glutamate 2 receptor, both for rats with mutant SOD1, and in
human patients with spinal and bulbar muscular atrophy. There could be
differences in the motor neuron diseases that might be important for considering
any therapeutic approaches.
View this Article »

Imaging Method Can Distinguish ALS from Other Motor Disorders

Magnetic Resonance Imaging (MRI) can tell apart patients with
ALS from patients with another motor disorder called progressive muscular
atrophy, according to findings published by Italian investigators in October in
Radiology. Luigi Murri M.D. and collaborators at the University of Pisa
used measures to detect diffusion along and across the fiber tracts coming down
from the brain through the spinal cord. They did this with a special technique
applied to the MRIs of a small number of patients. One of the measures changed
in ALS patients but not in the patients who did not have ALS. This difference
indicates a change in the nerve tracts descending from the brain. Further,
certain values derived from the imaging technique correlated with disease
severity and duration in ALS, lending hope that this type of imaging might be
able to monitor disease progression and aid testing of candidate treatments in
clinical trials. More patients would need to be tested to verify the findings.
View this Article »

Confirmation of RNA Inhibition (RNAi) as Possible ALS Strategy

In December's Journal of Biological Chemistry, Japanese
researchers confirmed the ability of RNAi to slow the progress of symptoms in
mice modeling ALS. The researchers created mice carrying a gene that shut down
the production of SOD1 by means of a small interfering RNA. They then bred these
mice to ones with mutant SOD1. Halting production of the mutant SOD1 protein
prevented the disease in the mice as reported by the team led by Hidehiro
Mizusawa, M.D., Ph.D. at the Tokyo Medical and Dental University. The RNA inhibition strategy differed from that reported earlier, but
both succeeded, supporting the hope that the general strategy will prove useful
as a therapeutic approach to inherited ALS due to SOD1 mutation.
View this Article »

A way to use RNA interference as a gene knock out approach in
mammalian systems is meanwhile proposed by Zuoshang Xu, M.D., Ph.D. and
colleagues at the University of Massachusetts in Worcester in a January
publication in the Public Library of Science Genetics. They suggest that
the RNAi technique can be used to generate models of disease such as ALS in
different species in order to better understand the disease process and devise
candidate treatment strategies.
View this Article »

Mitomycin C Reduces SOD1 by Nonspecific Cell Toxicity

Researchers led by Robert Brown Jr., D.Phil., M.D. at
Massachusetts General Hospital in Charlestown, Mass. showed an apparently
helpful action of a compound called mitomycin C is unlikely to prove of
therapeutic value. The treatment succeeds in reducing the amount of SOD1 mutant
protein in a lab test related to aspects of ALS, but the effect is most likely
due to a generalized toxin action on cells. When given to rodents directly into
the brain, the compound failed to produce any decline in SOD1 levels. These
cautionary findings were published in Neuroscience Letters in January and
speak to the pitfalls in designing new therapies for the disease.
View this Article »

Details of Neuron Demise in ALS Model

Dick Jaarsma, Ph.D. Erasmus University Rotterdam in the
Netherlands and colleagues published in October in the European Journal of
Neuroscience detailed observations on 'sick' motor neurons in a mouse model
of ALS. They found that motor neurons in these mice experience a prolonged sick
phase prior to their death and disappearance. The stressed cells pile up
material marked for disposal by ubiquitin, first in the endings of their fibers
and then in the cell body. Following is a disintegration of the cell structure
called the Golgi and the activation of stress factors such as the transcription
protein, ATF3. Subsequent changes in the cell body include the flattening of the
nucleus and the appearance of heat shock proteins. This accounting of the demise
of motor neurons in the mouse model should help focus on the key events that can
be targeted by therapeutic strategies.
View this Article »

Proteasomes Pumped up in ALS Model

The proteasomes that handle cell trash appear to be revved up
in a model of ALS, the mouse with the SOD1 mutation. Proteasomes show increased
activity specifically in the spinal cord, according to a report by researchers
led by Jeffrey Elliott, M.D. at the University of Texas Southwest Medical Center
in Dallas in December in Experimental Neurology. Further, the change is
apparent only in the astrocytes and microglia and not in spleen or liver.
Certain sub-units of the large protein complex that make up the proteasome
appear in increased amounts in the SOD1 mice as compared to control mice. The
components that are increased are those that respond to mediators of
inflammation. These findings suggest how inflammation and destruction of protein
may interact to produce ALS or may simply reflect the ongoing disease process.
View this Article »

Chaperones and ALS

Molecules that guide protein folding and destruction inside
cells, called chaperones, are also implicated in ALS. One chaperone, called the
glucose-regulated protein 78/BiP (GRP78), is located within the endoplasmic
reticulum, the protein assembly line. This chaperone appears trapped inside the
abnormal clumps of protein in sick neurons in the spinal cords of SOD1 mutant
mice, according to a report by Japanese researchers led by Hirofumi Kusaka
M.D., Ph.D. of Kansai Medical University in Osaka, as published in December in
Acta Neuropathologica. The chaperone's distribution mirrored that of
SOD1, supporting a suspect role for this chaperone in the disease.
View this Article »

Mutant SOD1 Stability and ALS: Prognosis and Disease Process

Mutant SOD1 proteins present in the red blood cells of ALS
patients can hint at how the disease will progress. If the mutant protein is
very unstable, that is, if it is less likely to be detectable in the cells, the
patient is likely to have shorter survival. These findings were reported in
December in Neurology by an international team led by Yoichi Yamamoto,
M.D., Ph.D. of Osaka University, Japan. But, the researchers noted, there are
exceptions to this apparent rule. Some patients live a decade or more with their
disease despite an unstable variant of the SOD1 protein. No one knows if making
the mutant SOD1 protein stable, that is, remain longer in cells, might provide a
way to treat the disease.
View this Article »

Another take on the stability of mutant SOD1 is the tendency
of the changed protein to unravel or to arrange itself incorrectly. The ability
of a cell to keep a protein properly folded or to recognize and get rid of
defective protein plays into diseases such as ALS that appear later in life and
are linked to deposits of damaged protein inside cells. Vassily Hatzimanikatis,
Ph.D. at Northwestern University, Evanston, Ill. and colleagues studied the
properties of folding proteins and concluded that the success of defense systems
inside cells have key implications for whether the disease develops. Their
findings using mathematical modeling are reported in February in Biophysical Journal.
View this Article »

A third report on mutant SOD1 proteins also models how the
various mutations in the protein linked with ALS cause the protein structure to
change, as published in the Journal of Molecular Biology in January by
Canadian researchers at the University of Waterloo, Ontario led by Elizabeth
Meiering, Ph.D.
View this Article »

Stem Cells Integrate Into Brain after Transplant

Researchers at the Salk Institute in La Jolla, Calif. showed
that human embryonic stem cells can integrate into the brain and make
connections after they are placed into fetal mice. According to findings
published by Fred Gage Ph.D. and colleagues online December 13 in The
Proceedings of the National Academy of Sciences, the stem cells formed
neurons and glia that had the same appearance as the surrounding mice brain
cells. The connections to surrounding mouse neurons also appear to be normal. No
tumors resulted from the stem cell grafts. The experimental procedure results in
a model system that should prove useful for drug design for neurodegenerative
disease with the potential to accelerate testing of candidate therapies.
View this Article »

Neural progenitor cells derived from human embryonic stem
cells also can integrate into brain and function, as published December 15 in
Gene Therapy by University of Wisconsin researcher Clive Svendsen, Ph.D. and
collaborators. These investigators had engineered the progenitors to produce the
helper molecule called glial-derived neurotrophic factor (GDNF) so that the
cells would pump out this trophic factor after transplant. In mice that modeled
Parkinson's disease, the cell grafts produced new nerve fibers that grew into
the damaged part of the brain responsible for the symptoms of this motor
disorder. Also, some success was achieved in placing these engineered cells into
aged monkeys. The findings give hope that repair of damaged structures in the
central nervous system can be carried out by engineered stem cells that serve as
delivery vehicles for nurturing molecules, a strategy this team is exploring for
ALS.
View this Article »

Are SOD1 Mutant Mice Smarter?

The SOD1 mutation in mice modeling ALS may give them an
advantage at spatial tasks prior to their loss of motor function. The transgenic
mice used to model the disease appear to have better spatial memory through the
brain structure called the hippocampus. This odd finding in fact may tie in with
ideas on how the transmitter glutamate is involved in the disease process and
may help explain the cognitive loss that can accompany the disorder in some
patients. Italian researchers led by Martine Ammassari-Teule, Ph.D. of the IRCCS
S. Lucia Foundation in Rome published these intriguing findings in February in
Experimental Neurology.
View this Article »